Sidestepping the Biopsy With New Tools to Spot Cancer

For people with cancer or suspected cancer, the biopsy is a necessary evil — an uncomfortable and somewhat risky procedure to extract tissue for diagnosis or analysis.

Lynn Lewis, a breast cancer patient in Brooklyn, has had her cancer analyzed an easier way: simple blood tests that are being called “liquid biopsies.”

Telltale traces of a tumor are often present in the blood. These traces — either intact cancer cells or fragments of tumor DNA — are present in minuscule amounts, but numerous companies are now coming to market with sophisticated tests that can detect and analyze them.

While the usefulness of the tests still needs to be proved, proponents say that because liquid biopsies are not invasive, they can be easier to repeat periodically, potentially tracking the disease as it evolves and allowing treatments to be adjusted accordingly.

“Being able to do it serially is a huge advantage,” said Dr. Pamela Munster, an oncologist at the University of California, San Francisco. “We can’t serially biopsy a patient’s liver.”

Early warning could be one use. One study published in The New England Journal of Medicine, for instance, showed that in some cases a liquid biopsy could detect the worsening of breast cancer five months before it could be seen by CT scans. That could allow an ineffective therapy to be abandoned earlier.

Some developers think that such blood tests might one day be used to screen healthy people, providing early detection of a wide variety of cancers, not just a single type as with mammograms or PSA tests.

Similar technology has already transformed prenatal testing. Down syndrome and other chromosomal abnormalities can now be detected in a fetus by analyzing fetal DNA in a sample of a pregnant woman’s blood. Such testing appears to be leading to a decline in such invasive tests as amniocentesis.

For all the potential of liquid biopsies, however, the developers of such tests for the most part have not yet established their accuracy and, more important, their usefulness. Does blood testing really help patients?

Ms. Lewis, 54, a self-employed lawyer who has been battling metastatic breast cancer for seven years, is a case in point.

In June, she had a test of tumor DNA fragments in her blood developed by a start-up called Guardant Health. It found a genetic mutation that suggested her disease would be susceptible to the drug Afinitor.

Image

Blood tests can be analyzed in a lab at Guardant Health. The tests are called “liquid biopsies.”CreditJim Wilson/The New York Times

Ms. Lewis, however, had previously tried Afinitor and it had stopped working. Nonetheless, she tried it again. And again, it didn’t work. A second test in December found several more mutations but did not lead to a clear choice of treatments.

But a different liquid biopsy found that at least some of Ms. Lewis’s cancer cells had abundant amounts of the protein Her2, which drives tumor growth. That had not been seen on her tissue biopsies, perhaps because such biopsies sample only a tiny bit of what is typically a heterogeneous tumor.

As a result, Ms. Lewis has just started on Herceptin and Tykerb, two drugs for Her2-positive cancers.

“You will have a chance to identify a treatment sometimes and sometimes not,” said Dr. Massimo Cristofanilli, director of the breast care center at Thomas Jefferson University in Philadelphia, who is treating Ms. Lewis and is a leading expert on liquid biopsies. Still, he said, “you are certainly much more advanced than going blindly.”

Lack of evidence of utility has hindered the acceptance of CellSearch, the first test to detect and count circulating tumor cells. Sold by Janssen Diagnostics, a subsidiary of Johnson & Johnson, it was first approved by the Food and Drug Administration in 2004.

Studies have clearly shown that having a large number of tumor cells in the blood is worrisome, increasing the probability that the cancer will worsen and the patient will die. But it is not always clear what to do with that information.

“To tell someone you have a high chance of a cancer coming back but we don’t know what to do” is not that useful, said Dr. Scott Kopetz, an associate professor at the M.D. Anderson Cancer Center in Houston.

One study, for instance, found that for breast cancer patients with high circulating tumor cells — a sign that their therapy was not working — switching therapies did not prolong survival.

Robert McCormack, head of technology, innovation and strategy for Janssen Diagnostics, said that even stopping an ineffective therapy early and avoiding side effects could be useful. He said the company was conducting other studies to show that using its test improves outcomes.

Some newer tests, including one that Janssen is trying to develop, will be able to not just count cells but also analyze them. Cynvenio Biosystems says its test can sequence 50 genes in the circulating tumor cells.

But some experts say the momentum is shifting to the newer approach of looking for DNA fragments not inside cells that enter the bloodstream when cancer cells die.

Image

Helmy Eltoukhy, left, chief executive of Guardant Health, with AmirAli Talasaz, president and chief technology officer, in the lab.CreditJim Wilson/The New York Times

Guardant raised $10 million from Sequoia Capital, the venture capital firm known for backing Apple, Google and, most recently, WhatsApp. Another start-up pursuing that approach, Boreal Genomics, raised $18 million in October from Arch Venture Partners and other investors. A third, Inostics, was acquired last fall by Sysmex, a Japanese diagnostics company.

Established laboratory equipment companies like Illumina, Bio-Rad Laboratories and RainDance Technologies hope their machines will be used to test for tumor DNA.

Trovagene is looking for tumor DNA fragments in urine instead of blood. And the team of Qiagen and Exosome Diagnostics is trying to find tumor information in exosomes, little globules of material released by cells into the blood.

Not all of these companies will survive or even get to market. One prominent entrant, On-Q-ity, has already folded, despite being backed by leading venture capitalists.

Many cancer centers have started doing genetic analyses of tumors using conventional biopsies, looking for mutations that can be treated with particular drugs. Foundation Medicine, a company that offers a test analyzing more than 200 genes from a traditional biopsy, has a market valuation of about $1 billion.

Doing such analysis on a blood sample is a greater technical challenge. Tumor DNA can represent as little as one ten-thousandth of the free-floating DNA in blood, the rest coming from healthy cells. Similarly, there will be millions or even billions of regular blood cells for every circulating tumor cell.

“It’s like looking at the sun and trying to see the stars,” said Nitin Sood, chief executive of Boreal Genomics. Mistakes can easily be made. And fewer genes can typically be analyzed from a liquid biopsy than from a conventional tumor biopsy.

The biggest impact would come if blood tests could detect cancer in seemingly healthy people, when it is still curable.

A recent study by researchers at Johns Hopkins University found that tumor DNA could be detected in the blood of about half the 223 patients with localized cancers that they tested.

However, since it was already known that those patients had cancer, the study did not demonstrate that a blood test could detect cancer earlier than other methods.

Ms. Lewis, the breast cancer patient, said she did not fully understand the results of the tumor mutation test.

Still, Ms. Lewis, whose tests have been done as part of research projects so she has not been billed, said she wanted whatever edge science can provide. “Now people are being treated more for their own makeup,” she said.

A version of this article appears in print on , on Page B1 of the New York edition with the headline: Sidestepping the Biopsy With New Tools to Spot Cancer. Order Reprints | Today’s Paper | Subscribe